Formulations useful in the treatment of male and female impotence

ABSTRACT

Pharmaceutical compositions containing: extracts of  Tribulus terrestris, Epimedium koreanum, Cinnamon cassia  in the weight ratio of 1.5-3.5:1-2:0.1-0.4 respectively; and optionally arginine or a physiologically equivalent ester, salt or precursor thereof. The compositions are useful in the treatment of male and female sexual dysfunctions. A method of treatment using the pharmaceutical compositions is also described.

DESCRIPTION OF THE INVENTION

The present invention relates to formulations which are useful in thetreatment of male and female sexual dysfunctions.

Sexual dysfunctions have considerable importance, and form the subjectof intensive biomedical research efforts. According to recentstatistics, the problem of impotence in its various forms (absence oflibido and erectile dysfunctions) affects some 70% of the populationaged approx. 50 and over. The degree of impotence in its various formsobviously varies in severity, especially among the elderly, where it isoften physiologically associated with other disorders such as heart orkidney disease.

The drugs now available to treat such dysfunctions, especially erectiledysfunction, include hormones such as testosterone, VIP, prostaglandinderivatives (PG_(S)), and cardiovascular agents such as papaverine,phenoxybenzamine and phentolamine.

However, none of these drugs provides a satisfactory, permanent solutionto the problem, because of the side effects they cause and the need foran intercavernous or intraurethral injection in the case of papaverineand PGE2, for example.

Recently, cGMP phosphodiesterase inhibitors have been developed whichare particularly useful in the treatment of impotence, and are active bythe oral route. One of these agents, called Sildenafil (WO 94/28902), isalready on the market.

Here again, however, the side effects are by no means negligible, andthe need for safer and more effective treatments is still strongly felt.

Numerous products of natural origin (mainly plant- but alsoanimal-based) are now being studied by modern pharmacology, on the basisof indications obtained from traditional medicine, to evaluate thepossible scientific basis for their empirical use.

Biochemical studies have demonstrated the great complexity of themechanisms involved in the physiological processes associated withsexual activity, such as penile and clitoral erection, vaginallubrication, ejaculation and orgasm.

Mediators such as nitric oxide (NO), the enzyme factors involved in themetabolism of the cAMP and cGMP messengers, the adrenergic receptors ofthe smooth muscle cell membranes, dopaminergic neurotransmitters, andthe receptors of PG_(S) or other hormones are the possible targets of apharmacological treatment for impotence and other sexual dysfunctions.

It is obviously difficult to provide a satisfactory solution to thisspecific problem, partly because in addition to the purely biochemicaland physiological aspects there are also environmental and psychologicalfactors which can further complicate the clinical picture of patientssuffering from sexual disorders.

It has now been found that a combination of extracts of medicinal plantswith specific properties, in certain quantity ratios, gives particularlysatisfactory therapeutic results in the treatment of male and femalesexual dysfunctions.

The invention relates in particular to pharmaceutical compositionscomprising:

-   -   extracts of Tribulus terrestris, Epimedium koreanum, Cinnamon        cassia in the weight ratio of 1.5-3.5:1-2:0.1-0.4 respectively;

and optionally

-   -   arginine or a physiologically equivalent ester, salt or        precursor thereof and a suitable carrier or excipient.

Extracts of Tribulus terrestris, Epimedium koreanum, Cinnamon cassia areknown and already used in some types of traditional medicine for similarpurposes but no association of them are known, especially in thespecific quantitative ratios stated above.

In particular, Tribulus terrestris extract is known to induce synthesisof testosterone, a hormone responsible for stimulating sexual desire inboth men and women; Epimedium koreanum extract, which is rich inprenylated flavonoids, has a vasodilating effect mediated by NO release,so that the extract performs a vasokinetic activity on the arteries andarterioles; and Cinnamon cassia extract indirectly stimulates the libidoby acting on the pleasure-related dopamine receptors.

However, the therapeutic results obtainable with the compositions of theinvention cannot be explained solely on the basis of the activity ofeach extract; in fact, it has surprisingly been found that when theextracts are associated in quantitative ratios different from thosestated above, they remain inactive, and can even aggravate the disorder.A real increase in sexual activity can therefore only be obtained byusing the extracts of the various plants in a precise ratio whichincreases both libido and the blood supply to the genital organs.

The weight ratio of extracts of Tribulus terrestris, Epimedium koreanumand Cinnamon cassia is preferably 2.5:1.5:0.2.

Arginine, its salt, ester or precursor, when used, is present in aquantitative ratio of between 0.5 and 1.5, preferably 1, to the plantextracts.

Extracts of the medicinal plants specified above, obtained byconventional techniques such as extraction with solvents orsupercritical fluids, can be used for the purposes of this invention.

However, the use of standardised extracts with a pre-determined contentof certain characteristic components of the extract is preferred: forexample, Tribulus terrestris extract will contain approx. 40% ofsaponins expressed as dioscin; Epimedium koreanum extract is preferablyan extract with a flavonoid content (expressed as ikarine) of approx.60%; and Cinnamon cassia extract preferably has a cinnamic aldehydecontent of approx. 70%.

When preparing the extracts, various parts of the plants can be used, asthey contain the active constituents in different concentrations.

The whole plant is used to prepare Epimedium koreanum extracts inparticular; Tribulus terrestris extracts are preferably obtained fromthe aerial parts and seeds of the plant. In both cases, the extractionis preferably carried out with a 40% ethanol/water mixture, attemperatures of 25-85° C., preferably at 50° C.

Cinnamon cassia extracts are preferably prepared by extraction from thebark of the trunk with carbon dioxide under supercritical pressureconditions of between 150 and 300 bars, preferably at 210 bars.

The extracts of Tribulus and Epimedium can be further enriched in activeprinciples by back-extraction of the concentrated aqueous extracts withwater-immiscible solvents, which extract with sufficient selectivityeither the flavonoids or the saponins, respectively. Suitable waterimmiscible or partially miscible solvents are preferably ethyl acetateor n-butanol; the solvents used, after drying, are concentrated todryness or to small volume, diluted with aprotic solvents such asaliphatic ethers or aliphatic or aromatic hydrocarbons, in which theactive principles are insoluble. Precipitation of the active principlesin aprotic solvents allows to remove undesired inert substances and toconcentrate the active principles.

The purification of the extract of Cinnamon cassia is not necessary, asthe extraction system is sufficiently selective.

The invention also relates to the use of extracts of Tribulusterrestris, Epimedium koreanum and Cinnamon cassia in the weight ratioof 1.5-3.5:1-2:0.1-0.4 respectively, and optionally arginine or aphysiologically equivalent esters, salts or precursors thereof, toprepare medicaments for the treatment of male and female sexualdysfunctions, and especially for the treatment of impotence, erectiledysfunctions, libido disorders, frigidity and anorgasmia.

As an alternative to the plant extracts, the corresponding isolatedactive ingredients may be used, particularly a combination of dioscin,ikarin and cinnamic aldehyde. The use of said combination for thepreparation of a medicament for the treatment of impotence, erectiledysfunction, libido disorders, frigidity and anorgasmia as well as themedicaments comprising said combination are further objects of theinvention.

The mixture of extracts of the invention must be taken chronically, notjust immediately before sexual intercourse, although in some individualsthe response takes place on the first treatment, within 30 minutes oftaking the drug.

Chronic administration of the compositions of the invention does notcause any significant side effects, is well tolerated, and does notalter the delicate hormone balances, especially the androgen/oestrogenbalance, which govern major physiological events in men and women suchas the andropause and the menopause.

Examples of suitable forms of administration of the compositions of theinvention include tablets, soft and hard gelatin capsules, suppositoriesand drinkable preparations containing unit doses of between 100 and 300mg of Tribulus terrestris extract and unit doses of the other componentsin accordance with the weight ratios specified above. Solid-phaseformulations such as unmodified-release or gastroresistant tablets ordrinkable liquid forms are particularly preferred.

The following examples are given to illustrate the invention rather thanto limit its scope.

EXAMPLE 1 Preparation of Coated Tablets

Each 700 mg coated tablet contains: Tribulus terrestris 250.00 mgEpimedium koreanum 150.00 mg Cinnamon cassia 20.00 mg L-arginine 100.00mg Soya polysaccharides 55.00 mg Silicon dioxide 14.00 mg Silicifiedmicrocrystalline cellulose 92.00 mg Magnesium stearate 4.00 mgHydroxypropyl methylcellulose 6.40 mg Talc 5.20 mg Titanium dioxide 2.00mg Glycerin 0.12 mg Polysorbate 80 0.80 mg Quinoline 0.43 mg Indigotine0.05 mg

EXAMPLE 2 Preparation of Hard Gelatin Capsules

Each 340 mg capsule contains: Tribulus terrestris 125.00 mg Epimediumkoreanum 75.00 mg Cinnamon cassia 10.00 mg L-arginine 50.00 mg Soyapolysaccharides 25.00 mg Silicon dioxide 7.00 mg Silicifiedmicrocrystalline cellulose 45.00 mg Magnesium stearate 1.50 mg Talc 1.50mg

EXAMPLE 3 Preparation of Soft Gelatin Capsules

Each 700 mg soft gelatin capsule contains: Tribulus terrestris 125.00 mgEpimedium koreanum 75.00 mg Cinnamon cassia 10.00 mg L-Arginine 50.00 mgSoya lecithin 20.00 mg Medium-chain triglycerides 100.00 mg Polysorbate80 10.00 mg Soya oil 300.00 mg Colloidal silicon dioxide 10.00 mg

EXAMPLE 4 Preparation of a Drinkable Solution

Each 10 mL vial contains: Tribulus terrestris 250.00 mg Epimediumkoreanum 150.00 mg Cinnamon cassia 20.00 mg L-arginine hydrochloride100.00 mg Glycerin 3000.00 mg Polysorbate 20 800.00 mg Propylene glycol1000.00 mg Acesulfame K 175.00 mg Sodium saccharine 40.00 mgNeohesperidine DC 2.50 mg Flavouring 300.00 mg Potassium sorbate 11.70mg Methyl paraben 8.30 mg Purified water q.s. to 10.00 mL

EXAMPLE 5 Preparation of a Soluble Granulate

Each 5000 mg sachet contains: Tribulus terrestris 250.00 mg Epimediumkoreanum 150.00 mg Cinnamon cassia 20.00 mg L-arginine hydrochloride100.00 mg Polysorbate 20 500.00 mg Acesulfame K 175.00 mg Sodiumsaccharine 40.00 mg Neohesperidine DC 2.50 mg Flavouring 300.00 mgInulin 1000.00 mg Mannitol 2412.50 mg

1. A pharmaceutical composition comprising: an extract of Tribulusterrestris, an extract of Epimedium koreanum, and an extract of Cinnamoncassia, and wherein the extract of Tribulus terrestris, extract ofEpimedium koreanum, and extract of Cinnamon cassia are in a weight ratioof 1.5-3.5:1-2:0.1-0.4, respectively; and a suitable carrier orexcipient.
 2. The composition as claimed in claim 1, wherein the weightratio of the extract of Tribulus terrestris, extract of Epimediumkoreanum and extract of Cinnamon cassia are 2.5:1.5:0.2.
 3. Thecomposition as claimed in claim 1, further comprising L-arginine orL-arginine hydrochloride.
 4. The composition as claimed in claim 3,wherein the weight ratio of the extract of Tribulus terrestris, extractof Epimedium koreanum, extract of Cinnamon cassia and L-arginine orL-arginine hydrochloride is 2.5:1.5:0.2:1.
 5. The composition as claimedin claim 3, containing Tribulus terrestris, an extract of Epimediumkoreanum, an extract of Cinnamon cassia extracts and L-arginine or Larginine hydrochloride respectively in weight ratios of1.5-3.5:1-2:0.1-0.4:0.5-1.5.
 6. A composition comprising: an extract ofTribulus terrestris, an extract of Epimedium koreanum, and an extract ofCinnamon cassia, and wherein the extract of Tribulus terrestris, extractof Epimedium koreanum, and extract of Cinnamon cassia are in a weightratio of 1.5-3.5:1-2:0.1-0.4, respectively.
 7. The composition asclaimed in claim 6, wherein the weight ratio of the extract of Tribulusterrestris, extract of Epimedium koreanum and extract of Cinnamon cassiaare 2.5:1.5:0.2.
 8. The composition as claimed in claim 6, furthercomprising L-arginine or L-arginine hydrochloride, wherein the extractof Tribulus terrestris; extract of Epimedium koreanum; extract ofCinnamon cassia; and L-arginine or L-arginine hydrochloride are inweight ratios of 1.5-3.5:1-2:0.1-0.4:0.5-1.5.
 9. The composition asclaimed in claim 7, wherein the weight ratio of the extract of Tribulusterrestris, extract of Epimedium koreanum, extract of Cinnamon cassiaand L-arginine or L-arginine hydrochloride is 2.5:1.5:0.2:1.
 10. Thecomposition according to claim 6, further comprising arginine or aphysiologically equivalent ester or salt.
 11. The composition accordingto claim 1, further comprising arginine or a physiologically equivalentester or salt.